Association Between Surgery Preference and Receipt in Ductal Carcinoma In Situ After Breast Magnetic Resonance Imaging: An Ancillary Study of the ECOG-ACRIN Cancer Research Group (E4112).

Importance: Guiding treatment decisions for women with ductal carcinoma in situ (DCIS) requires understanding patient preferences and the influence of preoperative magnetic resonance imaging (MRI) and surgeon recommendation. Objective: To identify factors associated with surgery preference and surgery receipt among a prospective cohort of women with newly diagnosed DCIS. Design, Setting, and Participants: A prospective cohort study was conducted at 75 participating institutions, including community practices and academic centers, across the US between March 25, 2015, and April 27, 2016. Data were analyzed from August 2 to September 24, 2021. This was an ancillary study of the ECOG-ACRIN Cancer Research Group (E4112). Women with recently diagnosed unilateral DCIS who were eligible for wide local excision and had a diagnostic mammogram within 3 months of study registration were included. Participants who had documented surgery and completed the baseline patient-reported outcome questionnaires were included in this substudy. Exposures: Women received preoperative MRI and surgeon consultation and then underwent wide local excision or mastectomy. Participants will be followed up for recurrence and overall survival for 10 years from the date of surgery. Main Outcomes and Measures: Patient-reported outcome questionnaires assessed treatment goals and concerns and surgery preference before MRI and after MRI and surgeon consultation. Results: Of the 368 participants enrolled 316 (86%) were included in this substudy (median [range] age, 59.5 [34-87] years; 45 women [14%] were Black; 245 [78%] were White; and 26 [8%] were of other race). Pre-MRI, age (odds ratio [OR] per 5-year increment, 0.45; 95% CI, 0.26-0.80; P = .007) and the importance of keeping one's breast (OR, 0.48; 95% CI, 0.31-0.72; P < .001) vs removal of the breast for peace of mind (OR, 1.35; 95% CI, 1.04-1.76; P = .03) were associated with surgery preference for mastectomy. After MRI and surgeon consultation, MRI upstaging (48 of 316 [15%]) was associated with patient preference for mastectomy (OR, 8.09; 95% CI, 2.51-26.06; P < .001). The 2 variables with the highest ORs for initial receipt of mastectomy were MRI upstaging (OR, 12.08; 95% CI, 4.34-33.61; P < .001) and surgeon recommendation (OR, 4.85; 95% CI, 1.99-11.83; P < .001). Conclusions and Relevance: In this cohort study, change in patient preference for DCIS surgery and surgery received were responsive to MRI results and surgeon recommendation. These data highlight the importance of ensuring adequate information and ongoing communication about the clinical significance of MRI findings and the benefits and risks of available treatment options.

Cryoablation Without Excision for Low-Risk Early-Stage Breast Cancer: 3-Year Interim Analysis of Ipsilateral Breast Tumor Recurrence in the ICE3 Trial.

BACKGROUND: The ICE3 trial is designed to evaluate the safety and efficacy of breast cryoablation, enabling women older than 60 years with low-risk early-stage breast cancers to benefit from a nonsurgical treatment and to avoid the associated surgical risks. METHODS: The ICE3 trial is a prospective, multi-center, single-arm, non-randomized trial including women age 60 years or older with unifocal, ultrasound-visible invasive ductal carcinoma size 1.5 cm or smaller and classified as low to intermediate grade, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. Ipsilateral breast tumor recurrence (IBTR) at 5 years was the primary outcome. A 3-year interim analysis of IBTR was performed, and the IBTR probability was estimated using the Kaplan-Meier method. RESULTS: Full eligibility for the study was met by 194 patients, who received successful cryoablation per protocol. The mean age was 75 years (range, 55-94 years). The mean tumor length was 8.1 mm (range, 8-14.9 mm), and the mean tumor width was 7.4 mm (range, 2.8-14 mm). During a mean follow-up period of 34.83 months, the IBTR rate was 2.06% (4/194 patients). Device-related adverse events were reported as mild in 18.4% and moderate in 2.4% of the patients. No severe device-related adverse events were reported. More than 95% of the patients and 98% of the physicians reported satisfaction with the cosmetic results at the clinical follow-up evaluation. CONCLUSIONS: Breast cryoablation presents a promising alternative to surgery while offering the benefits of a minimally invasive procedure with minimal risks. Further study within a clinical trial or registry is needed to confirm cryoablation as a viable alternative to surgical excision for appropriately selected low-risk patients.

Preoperative Breast MRI for Newly Diagnosed Ductal Carcinoma in Situ: Imaging Features and Performance in a Multicenter Setting (ECOG-ACRIN E4112 Trial).

Background There are limited data from clinical trials describing preoperative MRI features and performance in the evaluation of mammographically detected ductal carcinoma in situ (DCIS). Purpose To report qualitative MRI features of DCIS, MRI performance in the identification of additional disease, and associations of imaging features with pathologic, genomic, and surgical outcomes from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E4112 trial. Materials and Methods Secondary analyses of a multicenter prospective clinical trial from the ECOG-ACRIN Cancer Research Group included women with DCIS diagnosed with conventional imaging techniques (mammography and US), confirmed via core-needle biopsy (CNB), and enrolled between March 2015 and April 2016 who were candidates for wide local excision (WLE) based on conventional imaging and clinical examination results. DCIS MRI features and pathologic features from CNB and excision were recorded. Each woman without invasive upgrade of the index DCIS at WLE received a 12-gene DCIS score. MRI performance metrics were calculated. Associations of imaging features with invasive upgrade, dichotomized DCIS score (<39 vs ≥39), and single WLE success were estimated in uni- and multivariable analyses. Results Among 339 women (median age, 60 years; interquartile range, 51-66 years), most DCIS cases showed nonmass enhancement (NME) (195 of 339 [58%]) on MRI scans with larger median size than on mammograms (19 mm vs 12 mm; P < .001). Positive predictive value of MRI-prompted CNBs was 32% (21 of 66) (95% CI: 22, 44), yielding an additional cancer detection rate of 6.2% (21 of 339) (95% CI: 4.1, 9.3). MRI false-positive rate was 14.2% (45 of 318) (95% CI: 10.7, 18.4). No imaging features were associated with invasive upgrade or DCIS score (P = .05 to P = .95). Smaller size and focal NME distribution at MRI were linked to single WLE success (P < .001). Conclusion Preoperative MRI depicted ductal carcinoma in situ (DCIS) diagnosed with conventional imaging most commonly as nonmass enhancement, with larger median span than mammography, and additional cancer detection rate of 6.2%. MRI features of this subset of DCIS did not enable prediction of pathologic or genomic outcomes. Clinical trial registration no. NCT02352883 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Kuhl in this issue. An earlier incorrect version of this article appeared online. This article was corrected on August 4, 2021.

Correction to: A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer.

An amendment to this paper has been published and can be accessed via the original article.

A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer.

BACKGROUND: Cancer stem cells (CSCs) are purported to be responsible for tumor initiation, treatment resistance, disease recurrence, and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSCs. Reparixin, an investigational allosteric inhibitor of CXCR1, reduced the CSC content of human BC xenograft in mice. METHODS: In this multicenter, single-arm trial, women with HER-2-negative operable BC received reparixin oral tablets 1000 mg three times daily for 21 days before surgery. Primary objectives evaluated the safety of reparixin and the effects of reparixin on CSC and tumor microenvironment in core biopsies taken at baseline and at treatment completion. Signal of activity was defined as a reduction of ≥ 20% in ALDH+ or CD24-/CD44+ CSC by flow cytometry, with consistent reduction by immunohistochemistry. RESULTS: Twenty patients were enrolled and completed the study. There were no serious adverse reactions. CSC markers ALDH+ and CD24-/CD44+ measured by flow cytometry decreased by ≥ 20% in 4/17 and 9/17 evaluable patients, respectively. However, these results could not be confirmed by immunofluorescence due to the very low number of CSC. CONCLUSIONS: Reparixin appeared safe and well-tolerated. CSCs were reduced in several patients as measured by flow cytometry, suggesting targeting of CXCR1 on CSC. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT01861054. Registered on April 18, 2013.

Association of Magnetic Resonance Imaging and a 12-Gene Expression Assay With Breast Ductal Carcinoma In Situ Treatment.

IMPORTANCE: Advanced diagnostics, such as magnetic resonance imaging (MRI) and gene expression profiles, are potentially useful to guide targeted treatment in patients with ductal carcinoma in situ (DCIS). OBJECTIVES: To examine the proportion of patients who converted to mastectomy after MRI and the reasons for those conversions and to measure patient adherence to radiotherapy guided by the 12-gene DCIS score. DESIGN, SETTING, AND PARTICIPANTS: Analysis of a prospective, cohort, nonrandomized clinical trial that enrolled women with DCIS on core biopsy who were candidates for wide local excision (WLE) from 75 institutions from March 25, 2015, to April 27, 2016, through the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network trial E4112. INTERVENTIONS: Participants underwent breast MRI before surgery, and subsequent management incorporated MRI findings for choice of surgery. The DCIS score was used to guide radiotherapy recommendations among women with DCIS who had WLE as the final procedure and had tumor-free excision margins of 2 mm or greater. MAIN OUTCOMES AND MEASURES: The primary end point was to estimate the conversion rate to mastectomy and the reason for conversion. RESULTS: Of 339 evaluable women (mean [SD] age, 59.1 [10.1] years; 262 [77.3%] of European descent) eligible for WLE before MRI, 65 (19.2%; 95% CI, 15.3%-23.7%) converted to mastectomy. Of these 65 patients, conversion was based on MRI findings in 25 (38.5%), patient preference in 25 (38.5%), positive margins after attempted WLE in 10 (15.4%), positive genetic test results in 3 (4.6%), and contraindication to radiotherapy in 2 (3.1%). Among the 285 who had WLE performed after MRI as the first surgical procedure, 274 (96.1%) achieved successful breast conservation. Of 171 women eligible for radiotherapy guided by DCIS score (clear margins, absence of invasive disease, and score obtained), the score was low (<39) in 82 (48.0%; 95% CI, 40.6%-55.4%) and intermediate-high (≥39) in 89 (52.0%; 95% CI, 44.6%-59.4%). Of these 171 patients, 159 (93.0%) were adherent with recommendations. CONCLUSIONS AND RELEVANCE: Among women with DCIS who were WLE candidates based on conventional imaging, multiple factors were associated with conversion to mastectomy. This study may provide useful preliminary information required for designing a planned randomized clinical trial to determine the effect of MRI and DCIS score on surgical management, radiotherapy, overall resource use, and clinical outcomes, with the ultimate goal of achieving greater therapeutic precision. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02352883.

High-speed Intraoperative Assessment of Breast Tumor Margins by Multimodal Ultrasound and Photoacoustic Tomography.

Conventional methods for breast tumor margins assessment need a long turnaround time, which may lead to re-operation for patients undergoing lumpectomy surgeries. Photoacoustic tomography (PAT) has been shown to visualize adipose tissue in small animals and human breast. Here, we demonstrate a customized multimodal ultrasound and PAT system for intraoperative breast tumor margins assessment using fresh lumpectomy specimens from 66 patients. The system provides the margin status of the entire excised tissue within 10 minutes. By subjective reading of three researchers, the results show 85.7% [95% confidence interval (CI), 42.0% - 99.2%] sensitivity and 84.6% (95% CI, 53.7% - 97.3%) specificity, 71.4% (95% CI, 30.3% - 94.9%) sensitivity and 92.3% (95% CI, 62.1% - 99.6%) specificity, and 100% (95% CI, 56.1% - 100%) sensitivity and 53.9% (95% CI, 26.1% - 79.6%) specificity respectively when cross-correlated with post-operational histology. Furthermore, a machine learning-based algorithm is deployed for margin assessment in the challenging ductal carcinoma in situ tissues, and achieved 85.5% (95% CI, 75.2% - 92.2%) sensitivity and 90% (95% CI, 79.9% - 95.5%) specificity. Such results present the potential of using mutlimodal ultrasound and PAT as a high-speed and accurate method for intraoperative breast tumor margins evaluation.

A fiber optoacoustic guide with augmented reality for precision breast-conserving surgery.

Lumpectomy, also called breast-conserving surgery, has become the standard surgical treatment for early-stage breast cancer. However, accurately locating the tumor during a lumpectomy, especially when the lesion is small and nonpalpable, is a challenge. Such difficulty can lead to either incomplete tumor removal or prolonged surgical time, which result in high re-operation rates (~25%) and increased surgical costs. Here, we report a fiber optoacoustic guide (FOG) with augmented reality (AR) for sub-millimeter tumor localization and intuitive surgical guidance with minimal interference. The FOG is preoperatively implanted in the tumor. Under external pulsed light excitation, the FOG omnidirectionally broadcasts acoustic waves through the optoacoustic effect by a specially designed nano-composite layer at its tip. By capturing the acoustic wave, three ultrasound sensors on the breast skin triangulate the FOG tip's position with 0.25-mm accuracy. An AR system with a tablet measures the coordinates of the ultrasound sensors and transforms the FOG tip's position into visual feedback with <1-mm accuracy, thus aiding surgeons in directly visualizing the tumor location and performing fast and accurate tumor removal. We further show the use of a head-mounted display to visualize the same information in the surgeons' first-person view and achieve hands-free guidance. Towards clinical application, a surgeon successfully deployed the FOG to excise a "pseudo tumor" in a female human cadaver. With the high-accuracy tumor localization by FOG and the intuitive surgical guidance by AR, the surgeon performed accurate and fast tumor removal, which will significantly reduce re-operation rates and shorten the surgery time.

Prospective multicenter trial evaluating balloon-catheter partial-breast irradiation for ductal carcinoma in situ.

PURPOSE: To determine outcomes of accelerated partial-breast irradiation (APBI) with MammoSite in the treatment of ductal carcinoma in situ (DCIS) after breast-conserving surgery. METHODS AND MATERIALS: We conducted a prospective, multicenter trial between 2003 and 2009. Inclusion criteria included age >18 years, core needle biopsy diagnosis of DCIS, and no prior breast cancer history. Patients underwent breast-conserving surgery plus MammoSite placement. Radiation was given twice daily for 5 days for a total of 34 Gy. Patients were evaluated for development of toxicities, cosmetic outcome, and ipsilateral breast tumor recurrence (IBTR). RESULTS: A total of 41 patients (42 breasts) completed treatment in the study, with a median follow up of 5.3 years. Overall, 28 patients (68.3%) experienced an adverse event. Skin changes and pain were the most common adverse events. Cosmetic outcome at 6 months was judged excellent/good by 100% of physicians and by 96.8% of patients. At 12 months, 86.7% of physicians and 92.3% of patients rated the cosmetic outcome as excellent/good. Overall, 4 patients (9.8%) developed an IBTR (all DCIS), with a 5-year actuarial rate of 11.3%. All IBTRs were outside the treatment field. Among patients with IBTRs, the mean time to recurrence was 3.2 years. CONCLUSIONS: Accelerated partial-breast irradiation using MammoSite seems to provide a safe and cosmetically acceptable outcome; however, the 9.8% IBTR rate with median follow-up of 5.3 years is concerning. Prospective randomized trials are necessary before routine use of APBI for DCIS can be recommended.

Comparative evaluation of [(99m)tc]tilmanocept for sentinel lymph node mapping in breast cancer patients: results of two phase 3 trials.

BACKGROUND: Sentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [(99m)Tc]Tilmanocept is a novel receptor-targeted radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance. METHODS: A total of 13 centers contributed 148 patients with breast cancer. Each patient received [(99m)Tc]tilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and [(99m)Tc]tilmanocept. RESULTS: A total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by [(99m)Tc]tilmanocept for a concordance rate of 99.04 % (p < 0.0001). [(99m)Tc]tilmanocept detected a total of 320 nodes, of which 207 (64.7 %) were detected by VBD. [(99m)Tc]Tilmanocept detected at least 1 SLN in more patients (146) than did VBD (131, p < 0.0001). In 129 of 131 patients with ≥1 blue node, all blue nodes were radioactive. Of 33 pathology-positive nodes (18.2 % patient pathology rate), [(99m)Tc]tilmanocept detected 31 of 33, whereas VBD detected only 25 of 33 (p = 0.0312). No pathology-positive SLNs were detected exclusively by VBD. No serious adverse events were attributed to [(99m)Tc]tilmanocept. CONCLUSION: [(99m)Tc]Tilmanocept demonstrated success in detecting a SLN while meeting the primary endpoint. Interestingly, [(99m)Tc]tilmanocept was additionally noted to identify more SLNs in more patients. This localization represented a higher number of metastatic breast cancer lymph nodes than that of VBD.

A novel automated assay for the rapid identification of metastatic breast carcinoma in sentinel lymph nodes.

BACKGROUND: The authors prospectively evaluated the performance of a proprietary molecular testing platform using one-step nucleic acid amplification (OSNA) for the detection of metastatic carcinoma in sentinel lymph nodes (SLNs) in a large multicenter trial and compared the OSNA results with the results from a detailed postoperative histopathologic evaluation (reference pathology) and from intraoperative imprint cytology (IC). METHODS: In total, 1044 SLN samples from 496 patients at 11 clinical sites were analyzed. Alternate 1-mm sections were subjected to either detailed histopathologic evaluation with hematoxylin and eosin and pancytokeratin immunostaining or the OSNA Breast Cancer System, which was calibrated to detect tumor deposits >0.2 mm by measuring cytokeratin 19 messenger RNA. At 7 sites, IC was performed before permanent section. The OSNA results were classified as negative (<250 copies/µL), micrometastases (from ≥250 to <5000 copies/µL), or macrometastases (≥5000 copies/µL). RESULTS: The sensitivity and specificity of the OSNA breast cancer system compared with reference pathology were 77.5% (95% confidence interval, 69.7%-84.2%) and 95.8% (95% confidence interval, 94.3%-97.0%), respectively, before discordant case analyses (DCA). Sensitivity and specificity after DCA were 82.7% and 97.7%, and final concordance was 95.8%. Performance for invasive lobular carcinoma demonstrated 88.2% sensitivity (95% confidence interval, 63.6%-98.5%) and 98.5% specificity (95% confidence interval, 92%-100%). The sensitivity of OSNA was significantly better than that of IC (80% vs 63%; P = .0229). CONCLUSIONS: The OSNA breast cancer system proved to be highly accurate for the detection of metastatic breast cancer in axillary SLNs. Sensitivity was comparable to that predicted for conventional postoperative histologic examination at 2-mm intervals and was significantly more sensitive than IC. Automation, semiquantitative results enabling the differentiation of macrometastasis and micrometastasis, and rapid results render the assay suitable for intraoperative and/or permanent evaluation of SLNs.